2,2-Difluoro-16-phenoxy-PGA.sub.1 analogs

- The Upjohn Company

2,2-Difluoro prostaglandin E, F.sub..alpha., F.sub..beta., A and B analogs are disclosed with intermediates and with processes for making them. These compounds differ from the prostaglandins in that they have two fluoro atoms at the C-2 position in place of the two hydrogen atoms at C-2 in the prostaglandins. These compounds are useful for a variety of pharmacological purposes, including antiulcer, inhibition of platelet aggregation, increase in nasal patency, labor induction at term, and wound healing.

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Description

The present invention relates to prostaglandin analogs for which the essential material constituting a disclosure therefor is incorporated by reference here from U.S. Pat. No. 4,001,300, issued Jan. 4, 1977.

Claims

1. A compound of the formula ##STR1## or a mixture comprising that compound and the enantiomer thereof, WHEREIN G IS 2 TO 4, INCLUSIVE;

Wherein M.sub.1 is ##STR2## wherein R.sub.7 and R.sub.8 are hydrogen or methyl, with the proviso that one of R.sub.7 or R.sub.8 is methyl only when the other is hydrogen;
Wherein T is alkyl of one to 3 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR.sub.4 wherein R.sub.4 is alkyl of one to 3 carbon atoms, inclusive, and wherein s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl;
Wherein R.sub.1 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro, alkyl of one to 4 carbon atoms, inclusive, or a pharmacologically acceptable cation, ##STR3## WHEREIN R.sub.5 is hydrogen or methyl, with the proviso that R.sub.5 is methyl only when R.sub.7 and R.sub.8 are both hydrogen.

2. A compound according to claim 1, wherein M.sub.1 is ##STR4##

3. A compound according to claim 2, wherein g is 2.

4. A compound according to claim 3, wherein s is 0 or s is one and T is chloro, fluoro, or trifluoromethyl.

5. A compound according to claim 4, wherein R.sub.7 is methyl.

6. A compound according to claim 5, wherein s is 1 and T is trifluoromethyl.

7. 2,2-Difluoro-15-methyl-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetrano r-PGA.sub.1, a compound according to claim 6, wherein R.sub.1 is hydrogen.

8. 2,2-Difluoro-15-methyl-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetrano r-PGA.sub.1, methyl ester, a compound according to claim 6, wherein R.sub.1 is methyl.

9. A compound according to claim 5, wherein s is 1 and T is fluoro.

10. 2,2-Difluoro-15-methyl-16-(p-fluorophenoxy)-17,18,19,20-tetrano r-PGA.sub.1, a compound according to claim 9, wherein R.sub.1 is hydrogen.

11. 2,2-Difluoro-15-methyl-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGA.su b.1, methyl ester, a compound according to claim 9, wherein R.sub.1 is methyl.

12. A compound according to claim 5, wherein s is one and T is chloro.

13. 2,2-Difluoro-15-methyl-16-(p-chlorophenoxy)-17,18,19,20-tetranor-P GA.sub.1, a compound according to claim 12, wherein R.sub.1 is hydrogen.

14. 2,2-Difluoro-15-methyl-16-(p-chlorophenoxy)-17,18,19,20-tetranor-PGA.su b.1, methyl ester, a compound according to claim 12, wherein R.sub.1 is methyl.

15. A compound according to claim 5, wherein s is 0.

16. 2,2-Difluoro-15-methyl-16-phenoxy-17,18,19,20-tetranor-PGA.sub.1, a compound according to claim 15, wherein R.sub.1 is hydrogen.

17. 2,2-Difluoro-15-methyl-16-phenoxy-17,18,19,20-tetranor-PGA.sub.1, methyl ester, a compound according to claim 15, wherein R.sub.1 is methyl.

18. A compound according to claim 4, wherein R.sub.8 is methyl.

19. A compound according to claim 18, wherein s is one, and T is trifluoromethyl.

20. 2,2-Difluoro- 16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGA.sub.1, 15-methyl ether, a compound according to claim 19, wherein R.sub.1 is hydrogen.

21. 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-PG A.sub.1, 15-methyl ether, methyl ester, a compound according to claim 19, wherein R.sub.1 is methyl.

22. A compound according to claim 18, wherein T is fluoro.

23. 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGA.sub.1, 15-methyl ether, a compound according to claim 22, wherein R.sub.1 is hydrogen.

24. 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGA.sub.1, 15-methyl ether, methyl ester, a compound according to claim 22, wherein R.sub.1 is methyl.

25. A compound according to claim 18, wherein s is one and T is chloro.

26. 2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetra-nor-PGA.sub.1, 15-methyl ether, methyl ester, a compound according to claim 25, wherein R.sub.1 is hydrogen.

27. 2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-PGA.sub.1, 15-methyl ether, methyl ester, a compound according to claim 25, wherein R.sub.1 is methyl.

28. A compound according to claim 18, wherein s is 0.

29. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-PGA.sub.1, 15-methyl ether, a compound according to claim 28, wherein R.sub.1 is hydrogen.

30. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-PGA.sub.1, 15-methyl ether, methyl ester, a compound according to claim 28, wherein R.sub.1 is methyl.

31. A compound according to claim 4, wherein R.sub.7 and R.sub.8 are hydrogen.

32. A compound according to claim 31, wherein R.sub.5 is methyl.

33. A compound according to claim 32, wherein s is one and T is trifluoromethyl.

34. 2,2-Difluoro- 16-methyl-16-(m-trifluoromethylphenoxy)-18,19,20-trinor-PGA.sub.1, a compound according to claim 33, wherein R.sub.1 is hydrogen.

35. 2,2-Difluoro-16-methyl-16-(m-trifluoromethylphenoxy)-18,1 9,20-trinor-PGA.sub.1, methyl ester, a compound according to claim 33, wherein R.sub.1 is methyl.

36. A compound according to claim 32, wherein s is one and T is fluoro.

37. 2,2-Difluoro-16-methyl-16-(p-fluorophenoxy)-18,19,20-trinor-PGA.sub.1, a compound according to claim 36, wherein R.sub.1 is hydrogen.

38. 2,2-Difluoro-16-methyl-16-(p-fluorophenoxy)-18,19,20-trinor-PGA.sub.1, methyl ester, a compound according to claim 36, wherein R.sub.1 is methyl.

39. A compound according to claim 32, wherein s is one and T is chloro.

40. 2,2-Difluoro-16-methyl-16-(p-chlorophenoxy)-18,19,20-trinor-PGA.sub.1, a compound according to claim 39, wherein R.sub.1 is hydrogen.

41. 2,2-Difluoro-16-methyl-16-(p-chlorophenoxy)-18,19,20-trinor-PGA.sub.1, methyl ester, a compound according to claim 39, wherein R.sub.1 is methyl.

42. A compound according to claim 32, wherein s is 0.

43. 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-PGA.sub.1, methyl ester, a compound according to claim 42, wherein R.sub.1 is methyl.

44. 2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-PGA.sub.1, methyl ester, a compound according to claim 42, wherein R.sub.1 is methyl.

45. A compound according to claim 31, wherein R.sub.5 is hydrogen.

46. A compound according to claim 45, wherein s is one and T is trifluoromethyl.

47. 2,2-Difluoro- 16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGA.sub.1, a compound according to claim 46, wherein R.sub.1 is hydrogen.

48. 2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGA.sub.1, methyl ester, a compound according to claim 46, wherein R.sub.1 is methyl.

49. A compound according to claim 45, wherein s is one and T is fluoro.

50. 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGA.sub.1, a compound according to claim 49, wherein R.sub.1 is hydrogen.

51. 2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGA.sub.1, methyl ester, a compound according to claim 49, wherein R.sub.1 is methyl.

52. A compound according to claim 45, wherein s is one and T is chloro.

53. 2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-PGA.sub.1, a compound according to claim 52, wherein R.sub.1 is hydrogen.

54. 2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-PGA.sub.1, methyl ester, a compound according to claim 52, wherein R.sub.1 is methyl.

55. A compound according to claim 45, wherein s is 0.

56. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-PGA.sub.1, a compound according to claim 55, wherein R.sub.1 is hydrogen.

57. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-PGA.sub.1, methyl ester, a compound according to claim 55, wherein R.sub.1 is methyl.

58. The compound according to claim 1 wherein M.sub.1 is ##STR5##

Referenced Cited
U.S. Patent Documents
3775462 November 1973 Axen
Foreign Patent Documents
1,282,661 July 1972 UK
1,282,662 July 1972 UK
1,282,663 July 1972 UK
Patent History
Patent number: 4097519
Type: Grant
Filed: Sep 17, 1976
Date of Patent: Jun 27, 1978
Assignee: The Upjohn Company (Kalamazoo, MI)
Inventor: Udo F. Axen (Plainwell, MI)
Primary Examiner: Paul J. Killos
Attorney: Robert A. Armitage
Application Number: 5/724,239
Classifications
Current U.S. Class: Oxy In Acid Moiety (560/53); 260/520B; 260/404; 260/4045; 260/408
International Classification: C07C 6522; C07C17700;